An Unusual Case of Refractory Peptic Ulcer Disease

Question: A 14-year-old boy was admitted to our hospital with unprovoked episodic pain in the upper abdomen. Gastroscopy showed duodenal ulcer. Pathologic study revealed chronic mucosal inflammation and follicle formation. Helicobacter pylori (HP) was positive. He was given proton pump inhibitor plus gastric mucosal protective agent for 6 weeks and quadruple anti-HP therapy for 14 days. After a month of drug withdrawal, the symptoms relieved, and the 13C breath test was negative. However, symptoms recurred after 3 months and huge duodenal ulcer reappeared. Notably, after the second round of standard duodenal ulcer therapy, the ulcer became even wider (Figure A). After admission, elevations of eosinophils (5.6%), lymphocytes (53.1%), platelets (434 × 109/L), immunoglobulin (Ig) G4 (6.520 g/L), IgE (1567 U/mL), and gastrin (128 pg/mL) were noted, with decreased hemoglobin (94 g/L) and ferritin (2.2 ng/mL). His remaining blood tests, including liver and kidney function, coagulation function, tumor markers, high-sensitivity C-reactive protein levels, fecal calprotectin levels, antinuclear antibodies, antineutrophil cytoplasmic antibodies, antiphospholipid antibodies, immunoglobulin and complement, parasite IgG-were normal. Small bowel magnetic resonance imaging showed thickening of gastric antrum and duodenal bulb, with multiple enlarged lymph nodes. Gastroscopy showed huge ulcer on the anterior wall of the duodenal bulb. Colonoscopy showed the terminal ileum and colorectal mucosa to be generally normal. Endoscopic pathology revealed chronic inflammation of gastric and duodenal mucosa with eosinophil infiltration, the highest about 70 per high-power field (HPF) (Figure B, hematoxylin and eosin stain, ×200 magnification), IgG4 (+, 60 positive plasma cells per HPF), and IgG4+/IgG+ plasma cells >40% (Figure C, IgG4 staining, ×200 magnification); no eosinophilic infiltration or IgG4+ cells were found in biopsy of esophagus and terminal ileum. There was no granuloma. HP, cytomegalovirus, Epstein-Barr virus, and tuberculosis were all negative. What is the diagnosis? Look on page 337 for the answer and see the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. The patient met the diagnostic criteria for eosinophilic gastroenteritis and IgG4-related diseases, and Crohn’s disease cannot be excluded. In terms of treatment, as the patient was in adolescence and had great concerns about the side-effects of glucocorticoid and other drugs, he was treated with nasointestinal feeding and total enteral nutrition for 3 months. The IgG4 level decreased to 2.960 g/L when re-examined. Endoscopy showed that the duodenal ulcers were significantly reduced. Biopsy pathology showed decreased counts of eosinophils (6 eosinophils per HPF) and IgG4 cells (12 IgG4 cells per HPF) and decreased proportion of IgG4+/IgG+ plasma cells (<4%). Considering that the total enteral nutrition treatment was effective, it was recommended to switch to oral enteral nutrition. However, the patient found it difficult to control his diet at school and duodenal ulcer recurred after 2 months. Faced with the choice of the next step of treatment, a definitive diagnosis had to be made. We re-examined the histology of the patient‘s duodenal ulcer. There were both eosinophil and IgG4+ cell infiltration. Could the two be explained by a monophyletic hypothesis? It has been reported that IgG4 could mediate food allergen tolerance. The patient was then tested for food-intolerance IgG4, suggesting that the serum IgG4 levels for eggs, milk, soybeans, chicken, beef, and wheat were all higher than 2500 U/mL. Finally, the patient was diagnosed with food-specific IgG4-related refractory duodenal ulcer. It had been reported in the literature that IgG4 could mediate food allergen tolerance.1Yu W. Freeland D.M.H. Nadeau K.C. Food allergy: immune mechanisms, diagnosis and immunotherapy.Nat Rev Immunol. 2016; 16: 751-765Crossref PubMed Scopus (323) Google Scholar Some studies had found high levels of food allergen–specific IgG4 and low levels of IgE of patients with eosinophilic esophagitis (in both serum and mucosa samples). In these cases, IgG4 rather than IgE appeared to play a role in the induction and maintenance of immune tolerance to allergens, but the specific pathogenesis was unknown.2Schuyler A.J. Wilson J.M. Tripathi A. et al.Specific IgG4 antibodies to cow’s milk proteins in pediatric patients with eosinophilic esophagitis.J Allergy Clin Immunol. 2018; 142: 139-148.e12Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar The treatment of this disease is similar to that of eosinophilic gastroenteritis. Dietary therapy is the first choice, including empirical diet elimination and elemental diet. Hormone therapy can be considered if it is ineffective or the treatment compliance is poor. There are also reports on the application of biological agents, which is clinically inexperienced and not yet promoted.3Ebbo M. Grados A. Samson M. et al.Long-term efficacy and safety of rituximab in IgG4-related disease: data from a French nationwide study of thirty-three patients.PLoS One. 2017; 12e0183844Crossref PubMed Scopus (134) Google Scholar For our patient, oral glucocorticoids (0.75 mg/kg/d, gradually and regularly reduced in 3 months) were administered after full informed consent. The serum IgG4 level decreased to 0.86 g/L, and the IgG4 levels for eggs, soybeans, chicken, beef, and wheat were all lower than 500 U/mL. Gastroscopy showed gastric erosion and duodenal ulcer healing, no obvious eosinophils or IgG4+ cells were found in the tissue. After 12 months of follow-up, the patient achieved sustained mucosal and pathologic healing according to gastroscopy (Figure D).